Ribosomal Lesions Promote Oncogenic Mutagenesis

Area of Science:

• Molecular Biology
• Genetics
• Cancer Biology

Background:

• Ribosomopathies, caused by mutations in ribosomal proteins (RP) or assembly factors, lead to cellular hypoproliferation.
• These disorders paradoxically increase the risk of developing hyperproliferative cancers later in life.
• Somatic RP mutations are increasingly identified in various cancers, including T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL).

Purpose of the Study:

• To investigate the mechanisms by which RP mutations contribute to cancer progression.
• To understand the role of oxidative stress and secondary mutations in ribosomopathy-associated cancers.
• To explore the interplay between RP mutations, genomic instability, and oncogenic signaling pathways like NOTCH1.

Main Methods:

• Utilized mouse lymphoid cells with RPL10-R98S mutations to study proliferation defects and secondary mutation acquisition.
• Analyzed mutational load and specific genetic lesions in patients with T-ALL and CLL harboring RP mutations.
• Investigated the impact of NOTCH1 expression on cellular phenotypes, including oxidative stress and DNA damage, in RPL10-R98S cells.

Main Results:

• RPL10-R98S mutation leads to a proliferation defect due to elevated oxidative stress and DNA damage.
• RPL10-R98S cells acquire significantly more secondary mutations than wild-type cells, indicating genomic instability.
• RP mutations in T-ALL and CLL correlate with higher mutational burden, with enrichment in NOTCH1-activating lesions.
• NOTCH1 expression rescues RPL10-R98S-associated phenotypes, partly via downregulation of PKC-θ.

Conclusions:

• Ribosome dysfunction-induced oxidative stress causes hypoproliferation and cellular insufficiency in ribosomopathies and RP-mutant cancers.
• This cellular stress drives surviving cells to acquire rescuing mutations, potentiated by genomic instability, ultimately promoting hyperproliferation.
• Understanding these mechanisms is crucial for developing targeted therapies for ribosomopathy-associated cancers.